Tetrahydronaphthyridinyl-carboxamides having anti-convulsant activity

ABSTRACT

Compounds of formula (I) and pharmaceutically acceptable salts and solvates: where R 1  is hydrogen, C 1-6 alkyl (optionally substituted by hydroxy or C 1-4 alkoxy), phenyl-C 1-4 alkyl-, C 1-6 alkenyl, C 1-6 alkynyl; R 2  is hydrogen or, up to three substituents selected from halogen, NO 2 , CN, N 3 , CF 3 O—, CF 3 S—, CF 3 SO 2 —, CF 3 CO—, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 perfluoroalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl-, C 1-6 alkyl, C 1-6 alkylCO—, C 3-6 cycloalkylO—, C 3-6 cycloalkylCO—, C 3-6 cycloalkyl-C 1-4 alkylO—, C 3-6 cycloalkyl-C 1-4 alkylCO—, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C 1-4 alkyl-, C 1-6 alkylS—, C 1-6 alkylSO 2 —, (C 1-4 alkyl) 2 NSO 2 —, (C 1-4 alkyl)NHSO 2 —, (C 1-4 alkyl) 2 NCO—, (C 1-4 alkyl)NHCO— or CONH 2 ; or —NR 5 R 6  where R 5  is hydrogen or C 1-4 alkyl, and R 6  is hydrogen, C 1-4 alkyl, formyl, —CO 2 C 1-4 alkyl or —COC 1-4 alkyl; or two R 2  groups together form a carbocyclic ring that is saturated or unsaturated, optionally interrupted by O or NH; R 3  groups and R 4  groups are each independently hydrogen or C 1-6 alkyl and/or the two R 3  groups and/or the two R 4  groups together form a C 3-6 spiroalkyl group, provided that at least one R 3  or R 4  group is not hydrogen; and X is selected from hydrogen, halogen, cyano, alkyl and alkoxy, are useful in the treatment and prophylaxis of epilepsy, migraine, and other disorders.

This is a 371 of International Application PCT/GB99/01826, filed Jun. 9,1999, which claims priority from the following Great BritainApplication: 9812683.2, filed Jun. 12, 1998.

This invention relates to novel compounds, to processes for preparingthem, and to their use as therapeutic agents.

WO97/48683 (SmithKline Beecham) discloses that benzamide compounds offormula (A) below possess anti-convulsant activity and are thereforebelieved to be useful in the treatment and/or prevention of anxiety,mania, and related depression disorders.

where n and p are independently integers from 1 to 4 and (n+p) is from 2to 5;

R¹ is C₁₋₆alkylO—;

R² is hydrogen, halogen, CN, N₃, trifluoromethyldiazirinyl, CF₃, CF₃O—,CF₃S—, CF₃CO—, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C₁₋₄alkyl—,C₁₋₆alkylO—, C₁₋₆alkylCO—, C₃₋₆cycloalkylCO—,C₃₋₆cycloalkyl-C₁₋₄alkylCO—, phenyl, phenoxy, benzyloxy, benzoyl,phenyl-C₁₋₄alkyl—, C₁₋₆alkylS—, C₁₋₆alkylSO₂—, (C₁₋₄alkyl)₂NSO₂— or(C₁₋₄alkyl)NHSO₂—;

R³ is hydrogen, halogen, NO₂, CN, N₃, trifluoromethyldiazirinyl,C₁₋₆alkylO—, C₁₋₆alkylS—, C₁₋₆alkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₄alkyl-, C₁₋₆alkenyl, C₁₋₆alkynyl, CF₃CO—,C₁₋₆alkylCO—, C₃₋₆cycloalkylCO—, C₃₋₆cycloalkyl-C₁₋₄alkylCO—, phenyl,phenoxy, benzyloxy, benzoyl, phenyl-C₁₋₄alkyl-, or —NR⁵R⁶ where R⁵ ishydrogen or C₁₋₄alkyl, and

R⁶ is hydrogen, C₁₋₄alkyl, —CHO, —CO₂C₁₋₄alkyl or —COC₁₋₄alkyl;

R⁴ is hydrogen, C₁₋₆ alkyl, C₁₋₆alkenyl, or C₁₋₆alkynyl.

It has now been surprisingly found thattetrahydronaphthyridinyl-carboxamide compounds of formula (I) belowpossess anti-convulsant activity and are therefore believed to be usefulin the treatment and/or prevention of anxiety, mania, depression, panicdisorders and/or aggression, disorders associated with a subarachnoidhaemorrhage or neural shock, the effects associated with withdrawal fromsubstances of abuse such as cocaine, nicotine, alcohol andbenzodiazepines, disorders treatable and/or preventable withanti-convulsive agents, such as epilepsy including post-traumaticepilepsy. Parkinson's disease, psychosis, migraine, cerebral ischaemia.Alzheimer's disease and other degenerative diseases such as Huntingdon'schorea, schizophrenia, obsessive compulsive disorders (OCD),neurological deficits associated with AIDS, sleep disorders (includingcircadian rhythm disorders, insomnia & narcolepsy), tics (e.g. Giles dela Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia,especially trigeminal neuralgia, neuropathic pain, dental pain, cancerpain, inappropriate neuronal activity resulting in neurodysthesias indiseases such as diabetes, multiple sclerosis (MS) and motor neuronedisease, ataxias, muscular rigidity (spasticity), temporomandibularjoint dysfunction, and amyotrophic lateral sclerosis (ALS).

Accordingly, the present invention provides a compound of formula (I):

where R¹ is hydrogen, C₁₋₆alkyl (optionally substituted by hydroxy orC₁₋₄alkoxy), phenyl-C₁₋₄alkyl-, C₁₋₆alkenyl, or C₁₋₆alkynyl;

R² is hydrogen or up to three substituents selected from halogen, NO₂,CN, N₃, CF₃O—, CF₃S—, CF₃SO₂—, CF₃CO—, C₁₋₆alkyl, C₁₋₆alkenyl,C₁₋₆alkynyl, C₁₋₆perfluoroalkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₄alkyl-, C₁₋₆alkylO—, C₁₋₆alkylCO—, C₃₋₆cycloalkylO—,C₃₋₆cycloalkylCO—, C₃₋₆cycloalkyl-C₁₋₄alkylO—,C₃₋₆cycloalkyl-C₁₋₄alkylCO—, phenyl, phenoxy, benzyloxy, benzoyl,phenyl-C₁₋₄alkyl-, C₁₋₆alkylS—, C₁₋₆alkylSO₂—, (C₁₋₄alkyl)₂NSO₂—,(C₁₋₄alkyl)NHSO₂—, (C₁₋₄alkyl)₂NCO—, (C₁₋₄alkyl)NHCO— or CONH₂; or—NR⁵R⁶ where R⁵ is hydrogen or C₁₋₄alkyl, and R⁶ is hydrogen, C₁₋₄alkyl,formyl, —CO₂C₁₋₄alkyl or —COC₁₋₄alkyl; or two R² groups together form acarbocyclic ring that is saturated or unsaturated, optionallyinterrupted by O or NH;

R³ groups and R⁴ groups are each independently hydrogen or C₁₋₆ alkyland/or the two R³ groups and/or the two R⁴ groups together form a C₃₋₆spiroalkyl group, provided that at least one R³ or R⁴ group is nothydrogen; and X is selected from hydrogen, halogen, cyano, alkyl andalkoxy.

The compounds of this invention aretetrahydronaphthyridinyl-carboxamides, especially(tetrahydronaphthyridin-3-yl)carboxamides. The carboxamide moiety istypically a benzamide, but when two R² groups form a carbocyclic ring,this is typically a 5-7 membered ring, and the carboxamide moiety may bea naphthalene carboxamide or an indane carboxamide, or when interruptedby O or NH may be a benzofuran carboxamide or an indole carboxamide

In the formula (I), alkyl groups, including alkyl groups that are partof other moieties, such as alkoxy or acyl, may be straight chain orbranched. Phenyl groups, including phenyl groups that are part of othermoieties, in R² may optionally be substituted with one or moreindependently selected halogen or C₁₋₆ alkyl, C₁₋₆ alkoxy or C₁₋₆alkylcarbonyl.

Suitable C₃₋₆ cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl. Suitable halo substituents include fluoro,chloro, iodo and bromo.

It should be appreciated that compounds of the present invention possesschiral centres and as such may exist in different enantiomeric forms,the present invention extends to each enantiomeric form and mixturesthereof including diastereoisomers and racemates.

Preferably, the two R³ groups are the same, and the two R⁴ groups arethe same; typically either both R³ groups are gem-dialkyl orspiro-alkyl, preferably gem-dialkyl, and both R⁴ groups are hydrogen, orvice versa.

Accordingly one suitable group of compounds is of formula (IA)

A further suitable group is of formula (IB)

where R¹, R², R³, R⁴, X are as defined above.

A suitable group of compounds of formula (I) have

R¹ as hydrogen, methyl, ethyl, propyl, benzyl, hydroxyethyl,methoxyethyl.

R² as hydrogen or one or more of methyl, ethyl, n-butyl, iso-propyl,t-butyl, phenyl, methoxy, ethoxy, iso-propoxy, cyclopropylmethoxy,n-butoxy, phenoxy, benzyloxy, amino, acetylamino, nitro, azido, cyano,bromo, chloro, fluoro, iodo, acetyl, propionyl, pivaloyl, n-butyroyl,iso-butyroyl, benzoyl, iodobenzoyl, trifluoromethyl, perfluoroethyl,triflitoromethoxy, trifluoroacetyl, methanesulfonyl, n-propylsulfonyl,isopropylsulfonyl, dimethylsulfamoyl,

R³ one or both is hydrogen or methyl,

R⁴ one or both is hydrogen or methyl,

A preferred group of compounds of formula (I) have

R¹ as hydrogen, methyl,

R² as hydrogen or one or more of methyl, ethyl, i-propyl, t-butyl,methoxy, ethoxy, i-propoxy, bromo, chloro, cyano, trifluoromethyl,

R³ both methyl,

R⁴ both hydrogen.

Examples of compounds of formula (I) are:

N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)benzamide;

N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-iso-propylbenzamide;

N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamide;

N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-ethylbenzamide;

N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-ethoxybenzamide;

N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-chloro-4-iso-propyloxybenzamide;

N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-iso-propyloxybenzamide;

N-(5,6,7,8-tetrahydro-6,8,8-trimethy[1,6]naphthyridin-3-yl)-3-acetyl-4-iso-propyloxybenzamide;

N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-ethoxy-3-trifluoromethylbenzamide;

N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamide;

N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-methoxybenzamide;

N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-chloro-4-methoxybenzamide;

N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3yl)-3-cyano-4-methoxybenzamide;

N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-ethylbenzamide;

N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-methylbenzamide:

N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-pivaloylbenzamide;

N-(5,6,7,8-tetrahydro-6,8,8-trimethy[1,6]naphthyridin-3-yl)-5-chloro-2-methoxy-4-propyloxybenzamide;

N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-ethoxybenzamide;

N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoroacetylbenzamide;

N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)naphthalene-2-carboxamide;

N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-iso-propyloxybenzamide;

N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-acetyl-4-ethylbenzamide;

N-(5.6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-2,3-dihydrobenzofuran-5-carboxamide;

N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-n-butyroyl-4-methoxybenzamide;

N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-n-propionylbenzamide;

N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl-iso-butyroyl-4-methoxybenzamide;

N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-ethoxy-3-trifluoromethylbenzamide;

N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-acetyl-4-iso-propyloxybenzamide;

N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-methoxybenzamide;

N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-chloro-4-methoxybenzamide;

N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)4-methoxy-3-pentafluoroethylbenzamide;

N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)4-iso-propoxy-3-trifluoromethylbenzamide;

N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-ethyl-3)-trifluoromethylbenzamide;

N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3)-bromo-4-isyo-propylbenzamide;

N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3)-chloro4-ethoxybenzamide;

N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-fluoro-4-methoxybenzamide;

N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-pentafluoroethylbenzamide;

N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-fluoro-4-methoxybenzamide;

N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-propionylbenzamide,and;

N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-indole-2-carboxamide.

When synthesised, these compounds are often in salt form, such as thehydrochloride or trifluoroacetate, and such salts also form part of thisinvention. Such salts may be used in preparing pharmaceuticallyacceptable salts. The compounds and their salts may be obtained assolvates, such as hydrates, and these also form part of this invention.

The above compounds and pharmaceutically acceptable salts thereof,especially the hydrochloride, and pharmaceutically acceptable solvates,especially hydrates, form a preferred aspect of the present invention.

The administration of such compounds to a mammal may be by way of oral,parenteral, sub-lingual, nasal, rectal, topical or transdermaladministration.

An amount effective to treat the disorders hereinbefore describeddepends on the usual factors such as the nature and severity of thedisorders being treated and the weight of the mammal. However, a unitdose will normally contain 1 to 1000 mg, suitably 1 to 500 mg, forexample an amount in the range of from 2 to 400 mg such as 2, 5, 10, 20,30, 40, 50, 100, 200, 300 and 400 mg, of the active compound. Unit doseswill normally be administered once or more than once per day, forexample 1, 2, 3 4, 5 or 6 times a day, more usually 1 to 4 times a day,such that the total daily dose is normally in the range, for a 70 kgadult of 1 to 1000 mg, for example 1 to 500 mg, that is in the range ofapproximately 0.01 to 15 mg/kg/day, more usually 0.1 to 6 mg/kg/day, forexample 1 to 6 mg/kg/day.

It is greatly preferred that the compound of formula (I) is administeredin the form of a unit-dose composition, such as a unit dose oral,including sub-lingual, rectal, topical or parenteral (especiallyintravenous) composition.

Such compositions are prepared by admixture and are suitably adapted fororal or parenteral administration, and as such may be in the form oftablets, capsules, oral liquid preparations, powders, granules,lozenges, reconstitutable powders, injectable and infusable solutions orsuspensions or suppositories. Orally administrable compositions arepreferred, in particular shaped oral compositions, since they are moreconvenient for general use.

Tablets and capsules for oral administration are usually presented in aunit dose, and contain conventional excipients such as binding agents,fillers, diluents, tabletting agents, lubricants, disintegrants,colorants, flavourings, and wetting agents. The tablets may be coatedaccording to well known methods in the art. Suitable fillers for useinclude cellulose, mannitol, lactose and other similar agents. Suitabledisintegrants include starch, polyvinylpyrrolidone and starchderivatives such as sodium starch glycollate. Suitable lubricantsinclude, for example, magnesium stearate. Suitable pharmaceuticallyacceptable wetting agents include sodium lauryl sulphate.

These solid oral compositions may be prepared by conventional methods ofblending, filling, tabletting or the like. Repeated blending operationsmay be used to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are, of course,conventional in the art.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspensions, solutions, emulsions, syrups, or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents. for example sorbitol,syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats,emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample, almond oil, fractionated coconut oil, oily esters such asesters of glycerine, propylene glycol, or ethyl alcohol; preservatives,for example methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavouring or colouring agents. Oral formulationsalso include conventional sustained release formulations, such astablets or granules having an enteric coating.

For parenteral administration, fluid unit dose forms are preparedcontaining the compound and a sterile vehicle, The compound, dependingon the vehicle and the concentration, can be either suspended ordissolved. Parenteral solutions are normally prepared by dissolving thecompound in a vehicle and filter sterilising before filling into asuitable vial or ampoule and sealing. Advantageously, adjuvants such asa local anaesthetic, preservatives and buffering agents are alsodissolved in the vehicle. To enhance the stability, the composition canbe frozen after filling into the vial and the water removed undervacuum.

Parenteral suspensions are prepared in substantially the same mannerexcept that the compound is suspended in the vehicle instead of beingdissolved and sterilised by exposure to ethylene oxide before suspendingin the sterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound of the invention.

As is common practice, the compositions will usually be accompanied bywritten or printed directions for use in the medical treatmentconcerned.

Accordingly, the present invention further provides a pharmaceuticalcomposition for use in the treatment and/or prophylaxis of anxiety,mania, depression, panic disorders and/or aggression, disordersassociated with a subarachnoid haemorrhage or neural shock, the effectsassociated with withdrawal from substances of abuse such as cocaine,nicotine, alcohol and benzodiazepines, disorders treatable and/orpreventable with anti-convulsive agents, such as epilepsy includingpost-traumatic epilepsy, Parkinson's disease, psychosis, migraine,cerebral ischaemia, Alzheimer's disease and other degenerative diseasessuch as Huntingdon's chorea, schizophrenia, obsessive compulsivedisorders (OCD), neurological deficits associated with AIDS, sleepdisorders (including circadian rhythm disorders, insomnia & narcolepsy),tics (e.g. Giles de la Tourette's syndrome), traumatic brain injury,tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain,dental pain, cancer pain, inappropriate neuronal activity resulting inneurodysthesias in diseases such as diabetes, multiple sclerosis (MS)and motor neurone disease, ataxias, muscular rigidity (spasticity),temporomandibular joint dysfunction, and amyotrophic lateral sclerosis(ALS) which comprises a compound of formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, and a pharmaceutically acceptablecarrier.

The present invention also provides a method of treatment and/orprophylaxis of anxiety. mania, depression, panic disorders and/oraggression, disorders associated with a subarachnoid haemorrhage orneural shock, the effects associated with withdrawal from substances ofabuse such as cocaine, nicotine, alcohol and benzodiazepines, disorderstreatable and/or preventable with anti-convulsive agents, such asepilepsy including post-traumatic epilepsy Parkinson's disease,psychosis, migraine, cerebral ischaemia, Alzheimer's disease and otherdegenerative diseases such as Huntingdon's chorea, schizophrenia,obsessive compulsive disorders (OCD), neurological deficits associatedwith AIDS, sleep disorders (including circadian rhythm disorders,insomnia & narcolepsy), tics (e.g. Giles de la Tourette's syndrome),traumatic brain injure, tinnitus, neuralgia, especially trigeminalneuralgia, neuropathic pain, dental pain, cancer pain, inappropriateneuronal activity resulting in neurodysthesias in diseases such asdiabetes, multiple sclerosis (MS) and motor neurone disease, ataxias,muscular rigidity (spasticity), temporomandibular joint dysfunction, andamyotrophic lateral sclerosis (ALS) comprising administering to thesufferer in need thereof an effective or prophylactic amount of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof.

In a further aspect the invention provides the use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereoffor the manufacture of a medicament for the treatment and/or prophylaxisof anxiety, mania, depression, panic disorders and/or aggression,disorders associated with a subarachnoid haemorrhage or neural shock,the effects associated with withdrawal from substances of abuse such ascocaine, nicotine, alcohol and benzodiazepines, disorders treatableand/or preventable with anti-convulsive agents, such as epilepsyincluding post-traumatic epilepsy. Parkinson's disease, psychosis,migraine, cerebral ischaemia, Alzheimer's disease and other degenerativediseases such as Huntingdon's chorea, schizophrenia, obsessivecompulsive disorders (OCD), neurological deficits associated with AIDS,sleep disorders (including circadian rhythm disorders, insomnia &narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumaticbrain injury, tinnitus, neuralgia, especially trigeminal neuralgia,neuropathic pain, dental pain, cancer pain, inappropriate neuronalactivity resulting in neurodysthesias in diseases such as diabetes,multiple sclerosis (MS) and motor neurone disease, ataxias, muscularrigidity (spasticity), temporomandibular joint dysfunction, andamyotrophic lateral sclerosis (ALS).

In a further aspect the invention provides the use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate, thereofas a therapeutic agent, in particular for the treatment and/orprophylaxis of anxiety, mania, depression, panic disorders and/oraggression, disorders associated with a subarachnoid haemorrhage orneural shock, the effects associated with withdrawal from substances ofabuse such as cocaine, nicotine, alcohol and benzodiazepines, disorderstreatable and/or preventable with anti-convulsive agents, such asepilepsy including post-traumatic epilepsy. Parkinson's disease,psychosis, migraine, cerebral ischaemia. Alzheimer's disease and otherdegenerative diseases such as Huntingdon's chorea, schizophrenia,obsessive compulsive disorders (OCD), neurological deficits associatedwith AIDS, sleep disorders (including circadian rhythm disorders,insomnia & narcolepsy), tics (e.g. Giles de la Tourette's syndrome),traumatic brain injury, tinnitus, neuralgia, especially trigeminalneuralgia, neuropathic pain, dental pain, cancer pain, inappropriateneuronal activity resulting in neurodysthesias in diseases such asdiabetes, multiple sclerosis (MS) and motor neurone disease, ataxias,muscular rigidity (spasticity), temporomandibular joint dysfunction, andamyotrophic lateral sclerosis (ALS).

Another aspect of the invention is a process for the preparation ofcompounds of formula (I) as herein before described which comprisesreacting a compound of formula (II)

where R^(1A), R^(3A), and R^(4A) are R¹, R³ and R⁴ as defined forformula (I) or group or groups convertible to R¹, R³, and R⁴, and X isas defined for formula (I) with a compound of formula (III)

where Y is a leaving group such as Cl or OH, and R^(2A) groups areindependently R² as defined for formula (I) or a group or groupsconvertible to R², and where required converting an R^(1A), R^(2A),R^(3A), R^(4A) group to a R¹, R², R³, R⁴ group, converting one R¹, R²,R³, R⁴, X group to another R¹, R², R³, R⁴, X group, or separating anyenantiomers, or converting a salt product to the free base or anotherpharmaceutically acceptable salt or converting a free base product to apharmaceutically acceptable salt.

Conventional conditions for condensation of amines with carboxylic acidsor active derivatives thereof, such as acid chlorides, may be used. Forexample the amides and acids may be reacted in the presence of a mixtureof ethyl(dimethylaminopropyl)-carbodiimide/hydroxybenzotriazole in asuitable solvent such as dimethyl formamide, and amines and acidchlorides may be reacted together in a suitable solvent such as ethylacetate or dichloromethane, optionally in the presence of a base such astriethylamine.

Conversions of an R^(1A), R^(2A), R^(3A), R^(4A) group to a R¹, R², R³,R⁴ group typically arise when a protecting (group is needed during theabove coupling reaction or during the preparation of the reactants bythe procedures described below. Interconversion of one R¹, R², R³, R⁴, Xgroup to another typically arises when one compound of formula (I) isused as the immediate precursor of another compound of formula (I) orwhen it is easier to introduce a more complex or reactive substituent atthe end of a synthetic sequence.

Reaction of a compound of formula (III) which is an acid chloride (Y═Cl)typically results in formation of the hydrochloride salt of the compoundof formula (I). Hydrochloride salts may also be obtained by passing HClgas into a solution of the free base product, or adding a solution ofHCl in ether.

Compounds of formula (II) may be prepared from a compound of formula(IV),

by reaction with a dinitro-1-methylpyrid-2-one compound of formula (V)

in a solution of ammonia in a suitable solvent such as methanol, toobtain a compound of formula (VI) using a procedure similar to that ofS. Takada et al. J. Med. Chem. 1996, 39, 2844.

Compounds of formula (VI) may be converted to compounds of formula (II)by hydrogenation or reduction of the nitro group. For example, acompound of formula (VI) may be hydrogenated by treatment with hydrogenin a suitable solvent such as methanol in the presence of apalladium/carbon catalyst. Alternatively, a compound of formula (VI) maybe reduced with stannous chloride in concentrated hydrochloric acid in asuitable solvent such as ethanol.

Compounds of formula (IV) may be prepared using the procedures ofKatvalyan et al., Bull. Acad. Sci. USSR (Engl) 1968, 2436.

Compounds of formula (V) may be prepared using the procedure of E.Matsumura, M. Ariga and Y. Tohda, Bull, Chem. Soc. Japan, 52 (8),2413-2419 (1979).

Compounds of formula (III) may be prepared by further substitution ofcommercially available benzoic acid derivatives using conventionalprocedures, or by oxidation of corresponding substituted benzylalcohols. Alternatively benzoic acids can be prepared fromcorrepondingly substituted phenols, for example by formation of theacetate, coversion to an acetophenone and then to the desired acid.

Where the above described intermediates are novel compounds, they alsoform part of this invention.

The preparation of compounds of formula (II) is illustrated by thefollowing Descriptions; the preparation of compounds of formula (III) isillustrated by the following Preparations and Procedures; thepreparation of compounds of this invention is illustrated by thefollowing Examples. The utility of compounds of this invention is shownby the Pharmacological Data that follow the Examples.

Description 1

1,3,3-Trimethylpiperidin-4-one

The title compound was prepared according to the procedure of Katvalyanet al. Bull. Acad. Sci. USSR (Engl) 1968, 2436, b,p 70° C. at 16 mm Hg;^(m)/_(z) (API⁺); 142.1 (MH+)

Description 2

3-Nitro-5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridine

3,5-Dinitro-1-methylpyridin-2-one [prepared by the method of E.Matsumura, M. Ariga and Y. Tohda. Bull. Chem. Soc. Japan, 1979, 52,2413-2419] (2 g; 10 mmol) was suspended in MeOH (50 ml) and treated with0.88 aq, ammonia (10 ml; 157 mmol). 1,3,3-Trimethylpiperidin-4-one (1.7g; 12 mmol) was added and the mixture heated at 70° C. for 5 h. Themixture was cooled to room temperature then evaporated to dryness invacuo. The residue was digested with dichloromethane (2×50 ml) and thehot solution decanted from the red gum. The extracts were combined,evaporated to dryness in vacuo and the residue purified bychromatography on SiO₂, with 50% ethyl acetate: 60-80° C. petroleum togive the title compound as a yellow oil, which solidified on standing(1.05 g; 48%).

¹H NMR (250 MHz: CDCl₃) δ: 1.38 (6H, s), 2.47 (3H, s), 2.55 (2H, s),3.64 (2H, s), 8.09 (1H, d, J=3 Hz), 9.25 (1H, d, J=3 Hz); ^(m)/_(z)(API⁺); 222.1 (MH+)

Description 3

3-Amino-5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridine

The product from Description 2 (930 mg; 4.20 mmol) was dissolved in MeOH(30 ml) and the mixture treated with 10% palladium on carbon (150 mg)then hydrogenated at STP until hydrogen uptake ceased. Catalyst wasremoved by filtration through Celite and the filtrate and washingscombined and evaporated to dryness in vacuo. The residue was trituratedunder diethyl ether containing a little dichloromethane and the titlecompound collected by filtration, washed with diethyl ether and dried invacuo (795 mg; 84%).

¹H NMR (250 MHz; CD₃OD) δ_(H); 1.73-1.99 (2H, m), 2.34-2.55 (5H, m),2.63 (1H, d, J=17 Hz), 3.29 and 3.36 (1H, dd, J=17.5 Hz), 3.66-3.71 (1H,m), 3.99 (1H, d, J=6 Hz), 6.95 (1H, d, J=3 Hz), 7.95 (1H, d, J=3 Hz);^(m)/_(z) (API⁺); 190.16 (MH+).

Preparation 1

3-Bromobenzyl TBMS Ether

To a solution of 3-bromobenzyl alcohol (5.00 g. 0.027 mole) indichloromethane (30 ml), Et₃N (4.2 ml, 0.03 mole) was added a 1Msolution tert-butyldimethylsilyl chloride in dichloromethane (28.0 ml)dropwise. The mixture was allowed to stir at room temperature overnight,then water (30 ml) was added. The organic layer was washed with brine,dried (Na₂SO₄) and evaporated to give a red oil which was purified byflash chromatography on silica gel using 20% ether in hexane to give acolouorless oil (8.0 g).

Preparation 2

3-Pivaloylbenzylalcohol TBDMS Ether

n-Butyllithium (2.80 ml, 7.00 mmol, 2.5 M in hexane) was slowly added toa solution of Preparation 1 TBDMS ether (1.80 g, 6.0 mmol) in dry THF(10 ml) over 5 min at −78° C. The reaction mixture was maintained underargon at −78° C. for 1 h, and N,O-dimethyl-hydroxy pivaloyl amide (0.86g, 6.60 mmol) in THF (2 ml) was added dropwise with stirring at −78° C.The resulting mixture was allowed to stir at −78° C. for 2.5 h, quenchedwith NH₄Cl solution and allowed to warm to room temperature. The mixturewas extracted with ether (2×50 ml), the combined organics were dried(Na₂SO₄) and concentrated in vacuo to give the title compound as acolourless oil (1.75 g ^(m)/_(z) (API+); 307 (MH⁺; 8%).

Preparation 3

3-Pivaloylbenzylalcohol

The ether of Preparation 2 (1.47 g, 4.80 mmol) was dissolved in methanol(25 ml); conc. HCl (20 drops) was added and the whole allowed to stir atroom temperature for 4 h. Saturated NaHCO₃ solution was added and themixture extracted with ether (2×50 ml). The organic layer was dried oversodium sulfate and evaporation in vacuo gave title compound as acolourless oil (0.80 g). ^(m)/_(z) (API+); 193 (MH⁺; 17%).

Preparation 4

3-Pivaloylbenzoic Acid

3-Pivaloylbenzyl alcohol (0.80 g, 4.16 mmol) was dissolved in dioxane(20 ml). A solution of KOH (0.35 g, 6.30 mmol) in water (5 ml) was addedfollowed by KMnO₄ (1.45 g, 9.17 mmol). The mixture was stirred at roomtemperature over the weekend. The solution was filtered through Celiteand extracted with ether. The aqueous phase was acidified with dil. HCland extracted with ether (3×50 ml). The organic layer was dried overmagnesium sulphate and concentrated in vacuo to afford the titlecompound as a white solid (0.80 g).

¹H NMR (250 MHz, CDCl₃) δ: 1.38 (9H, s), 7.55 (1H t), 7.92 (1H, d, J=6.5Hz), 8.20 (1H, d, J=6.5 Hz), 8.44 (1H, s).

Preparation 5

3-Trifluoroacetylbenzoic Acid

The title compound was prepared from diethyl trifluoroacetamide and3-bromobenzyl TBDMS ether using a method similar to that described inPreparations 1, 2, 3 and 4, ^(m)/_(z) (API−); 217 (M-H⁺; 20%).

Preparation 6

Methyl 3-Chloro-4-iso-propoxybenzoate

Methyl 3-chloro-4-hydroxybenzoate (5 g, 26.8 mmol) in DMF (45 ml) wastreated with potassium carbonate (7.41 g, 53.6 mmol), 2-iodopropane(3.85 ml 40.2 mmol) and then stirred at 25° C. for 18 h. Work-up withethyl acetate Wave the title compound (6.1 g).

Preparation 7

3-Chloro-4-iso-propoxybenzoic Acid

Methyl 3-chloro-4-iso-propoxybenzoate (5.5 g, 24.1 mmol) was hydrolysedusing 1M NaOH (36 ml) in methanol (80 ml). Extraction and work-up withethyl acetate gave the title compound (4.3 g).

¹H NMR (DMSO-D₆) δ: 1.33 (6H, d), 4.79 (1H, m), 7.24 (1H, d), 7.87 (2H,m).

Preparation 8

3-Bromo-4-ethoxybenzoic Acid

The title compound was prepared from 4-ethylbenzoic acid in a mannersimilar to that of Procedure 1.

¹H NMR (DMSO-D₆) δ: 1.45 (3H, t, J=7 Hz), 4.26 (2H, q, J=7 Hz), 7.26(1H, d, J=9 Hz), 7.98 (1H, dd, J=2.9 Hz), 8.12 (1H, d, J=2 Hz).

Preparation 9

3-Bromo-4-ethylbenzoic Acid

The title compound was prepared from 4-ethylbenzoic acid in a mannersimilar to that of Procedure 1.

¹H NMR (DMSO-D₆) δ: 1.20 (3H, t, J=7 Hz), 2.78 (2H, q, J=7 Hz), 7.50(1H, d, J=8 Hz), 7.90 (1H, dd, J=2.8 Hz), 8.07 (1H, d, J=8 Hz).

Preparation 10

3-Cyano-4-iso-propylbenzoic Acid

The title compound was prepared from 4-iso-propylbenzoic acid using amanner similar to that described in Procedures 1 and 5.

¹H NMR (DMSO-D₆) δ: 1.07 (6H, d, J=7 Hz), 3.13 (1H,m, overlapped), 7.48(1H, d, J=7 Hz), 7.96 (1H, dd, J=2.8 Hz)), 8.00 (1H, d, J=2 Hz).

Preparation 11

4-Methoxy-3-trifluoromethylbenzoic Acid

The title compound was prepared from 3-bromo-4-methoxybenzoic acid andpotassium trifluoroacetate in a manner similat to that of Procedures 3and 4.

¹H NMR (DMSO-D₆) δ: 3.78 (3H, s), 7.18 (1N, d, J=9 Hz), 7.90 (1H, d, J=2Hz), 8.00 (1H, dd, J=2.9 Hz), 12.70-13.10 (1H, br,exchangeable)

Preparation 12

4-Methoxy-3-trifluoromethylbenzoyl Chloride

The title compound was prepared from 4-methoxy-3-trifluoromethylbenzoicacid with oxalyl chloride and DMF in chloroform at room temperature [D.Levin, Chem. Br., 1977, 20] followed by evaporation in vacuo.

Preparation 13

Methyl 3-Bromo-4-iso-propoxybenzoate

Methyl 3-bromo-4-hydroxybenzoate (2.5 g, 10.8 mmol) in DMF (35 ml) wastreated with potassium carbonate (3.0 g, 21.6 mmol), 2-iodopropane(2.76, 21.6 mmol) and then stirred at 25° C. for 48 h. Work-up withethyl acetate gave the title compound (3.0 g).

¹H NMR (250MHz, CDCl₃) δ: 1.41 (6H, d, J=7 Hz), 3.89 (3H, s), 4.66 (1H,m), 6.90 (1H, d, J=8 Hz), 7.93 (1H, dd, J=8.2 Hz), 8.22 (1H, d, J=2 Hz).

Preparation 14

Methyl 3-Cyano-4-iso-propoxybenzoate

Methyl 3-bromo-4-iso-propoxybenzoate (2.0 g, 7.3 mmol) andcopper(I)cyanide in N-methyl pyrrolidone (50 ml) was heated undervigorous reflux for 4 h. Work-up with ethyl acetate Pave the titlecompound (1.0 g).

¹H NMR (250MHz, CDCl₃) δ: 1.56 (6H, d, J=7 Hz), 4.05 (3H, s), 4.88 (1H,m), 7.13 (1H, d, J=8 Hz), 8.31 (1H, dd, J=8.2 Hz), 8.38 (1H, d, J=2 Hz)

Preparation 15

Methyl 3,5 Dichloro-4-ethoxybenzoate

The title compound was prepared in 69% yield from methyl3,5-dichloro-4-hydroxybenzoic acid and iodoethane in a manner similar tothat of Preparation 6.

¹H NMR (250MHz, CDCl₃) δ: 1.47 (3H, t, J=7 Hz), 3.91 (3H, s), 4.16 (2H,q, J=7.96 (2H, s).

Preparation 16

3-Methanesulfonyl-4-iso-propylbenzoic Acid

3-Chlorosulfonyl-4-iso-propylbenzoic acid (2.62 g, 10 mmol) [made from4-iso-propyl benzoic acid in a manner similar to that described inProcedures 7 and 8] was added slowly to a slurry of NaHCO₃ (2.52 g, 30mmol) and Na₂SO₃ (1.26 g 10 mmol) in water (9 ml) at 75° C. The mixturewas stirred for 1 h and then treated with bromoacetic acid (2.08 g, 15mmol) and NaOH (0.60 g, 15 mmol). The temperature was raised to 105° C.and the mixture heated at reflux for 24 h. The mixture was cooled,acidified to pH 1 and the resultant precipitate collected, washed anddried to give the title compound (1.43 g, 59%).

¹H NMR (250 MHz, acetone-D6) δ: 1.24 (6H, d, J=7 Hz), 3.13 (3H, s), 3.88(1H, m), 7.72 (1H, d, J=7 Hz), 8.15 (1H, dd, J=7 Hz), 8.52 (1H, d, J=7Hz).

Preparation 17

3-Chloro-4-ethoxybenzoic Acid

¹H NMR (DMSO-D₆) δ: 1.39 (3H, t, J=7 Hz), 4.20 (2H, q, J=7 Hz), 7.22(1H, d, J 7 Hz), 7.87 (2H, m).

Preparation 18

3-Bromo-4-iso-propoxybenzoic Acid

The title compound was prepared using a method similar to that ofPreparation 7.

¹H NMR (DMSO-D₆) δ: 1.29 (6H, d, J=7 Hz), 4.77 (1H, sep, J=7 Hz), 7.20(1H, d, J=8 Hz), 7.87 (1H, dd, J=8.2 Hz), 8.02 (1H, d, J=2 Hz), 12.92(1H, brs).

Procedure 1

5-Bromo-2,4-dimethoxybenzoic Acid

To a solution of 2.4-dimethoxybenzoic acid (4.0 g, 0.022 mol) inchloroform (60 ml) was added bromine (1.13 ml, 0.022 mol) in chloroform(20 ml) dropwise. After stirring overnight at room temperature theprecipitate was filtered off and dried to afford the title compound as awhite solid (2.87 g).

Procedure 2

5-Bromo-4-iso-propyl-2-methoxybenzoic Acid

To a solution of 2-methoxy-4-iso-propyl benzoic acid (7.0 g, 36.0 mmol)in chloroform (100 ml) was added bromine (1.86 ml) in chloroform (20 ml)dropwise. The reaction was stirred at room temperature overnight.Evaporation in vacuo afforded an oil (9.27 g), ^(m)/_(z) (CI); 275, 273(MH⁻; 70%).

Procedure 3

Methyl-5-bromo-4-iso-propyl-2-methoxy Benzoate

5-Bromo-4-iso-propyl-2-methoxybenzoic acid (9.268 g 34.0 mmol) wasdissolved in ethanol (250 ml) and conc. H₂SO₄ (2 ml) added. The mixturewas refluxed for 5 h and concentrated in vacuo. Residual material wastaken up into ethyl acetate and water, and the organic layer, dried(MgSO₄). Concentration in vacuo afforded an oil, which was purified byBiotage Column Chromatography on silica gel using 10% ether in hexane togive an oil (5.5 g).

Procedure 4

2,4-Dimethoxy-5-trifluoro methylbenzoic Acid

2,4-Dimethoxy-5-bromobenzoic acid methyl ester (1.5 g; 5.4 mmol) in DMF(25 ml) and toluene (8 ml) under argon was treated with potassiumtrifluoroacetate (1.53 g; 10.1 mmol) and copper (I) iodide (2.1 g, 10.9mmol). The mixture was heated to 170° C. with removal of water(Dean/Stark), and then at 155° C. overnight. The mixture was allowed tocool, poured into ether and water and filtered through Kieselguhr. Theorganic layer was dried (Na₂SO₄) and concentrated in vacuo to five abrown solid. Chromatography on Kieselgel 60 with 1:1 ether/petrol gave asolid (1.03 g) which was hydrolysed in 1:1 methanolic: aqueous NaOH (50ml) at 50° C. Work-up gave the title compound as a white solid (1 g).

Procedure 5a

Methyl 2-methoxy-5-cyano-4-iso-propylbenzoate

Copper (I) cyanide (550 mg, 6 mmol) was added to a solution of methyl2-methoxy-5-bromo-4-iso-propylbenzoate (861 mg) inN-methyl-2-pyrolidinone (30 ml). The mixture was stirred under argon andboiled under reflux for 4 h. The mixture was cooled, poured into excessice/water and ethyl acetate and filtered. The organic phase wasseparated, washed with water, brine and dried(MgSO₄). Evaporation gave acrude brown solid which was purified by chromatography on silica geleluting with ethyl acetate/n-hexane (1:4). The product was obtained as awhite solid (523 mg).

¹H NMR (250 MHz, CDCl₃) δ: 1.33 (6H, d, J=7 Hz), 3.38 (1H, sep, J=7 Hz),3.89 (3H, s), 3.98 (3H, s), 6.91 (1H, s), 8.08 (1H, s); ^(m)/_(z)(API⁺); 234 (MH⁺, 30%).

Procedure 5b

2-Methoxy-5-cyano-4-iso-propylbenzoic Acid

2N NaOH (1.25 ml) was added to a solution of the methyl ester P5a (490mg) in methanol (10 ml). The solution was stirred overnight at roomtemperature. The solution was then diluted with water, concentrated invacuo and washed with ethyl acetate. The aqueous phase was thenacidified with 2N HCl and extracted with ethyl acetate. The extract waswashed with brine, dried (MgSO₄) and evaporated to dryness giving theproduct as a white solid (418 mg).

¹H NMR (250MHz, CDCl₃) δ: 1.35 (6H, d, J=7 Hz), 3.43 (1(H, sep, J=7 Hz),4.14 (3H, s), 7.00 (1H, s), 8.41 (1H, s); ^(m)/_(z) (API⁺); 220 (MH⁺,100%).

Procedure 6a

Ethyl 2-ethoxy-4-iso-propyl-5-cyanobenzoate

Ethyl 2-ethoxy-4-iso-propyl-5-bromobenzoate (1.2 g, 3.8 mmol) wastreated with copper (I) cyanide (682 mg, 7.6 mmol) inN-methyl-2-pyrrolidinone (40 ml) as described in Procedure 5 to give thetitle compound as an oil (400 mg).

¹H NMR (250MHz, CDCl₃) δ: 1.12 (6H, d, J=7 Hz), 1.30 (3H, t, J=7 Hz),1.84 (3H, t, J=7 Hz), 3.17 (1H, sep, J=7 Hz), 3.99 (2H, q, J=9 Hz), 4.16(2H, q, J=7 Hz), 6.69 (1H, s), 7.86 (1 H, s); ^(m)/_(z) (API⁺); 262(MH⁺, 100%).

Procedure 6b

2-Ethoxy-4-iso-propyl-5-cyanobenzoic Acid

The ester P6a (370 mg, 1.41 mmol) was dissolved in methanol (5 ml) andover a 24 h period 1N NaOH (2.1 ml, 2.1 mmol) was added. The solutionwas concentrated under vacuum, diluted with water and washed with ethylacetate, The aqueous phase was acidified with 2N HCl and extracted withethyl acetate. The extract was washed with brine, dried (Mg SO₄) andevaporated to give the title acid (306 mg).

¹H NMR (250 MHz CDCl₃) δ: 1.39 (3H, d, J=7 Hz), 1.66 (3H, t, J=7 Hz),3.47 (1H, sep, J=7 Hz), 4.46 (2H, q, J=7 Hz), 7.03 (1H, s), 8.47 (1H,s); ^(m)/_(z) (API⁺); 234 (MH⁺, 100%).

Procedure 7

4-Ethoxy-2-methoxy-5-methylsulfonylbenzoic Acid

4-Ethoxy-2-methoxy-5-chlorosulfonyl benzoic acid in a 49% yield, wasprepared in 49% yield using the procedure of M. W. Harrold et al., J.Med. Chem., 1989, 32 874. This was used according, to the method of R.W. Brown. J. Org. Chem., 1991, 56, 4974 to the title compound in 19%yield.

¹H NMR (DMSO-D₆) δ: 1.30 (3H, t), 3.10 (3H, s), 3.83 (3H, s), 4.24 (2H,q), 6.73 (1H, s), 8.07 (1H, s).

Procedure 8

4-iso-propyl-2-methoxy-5-methylsulfonylbenzoic Acid

This was prepared in a similar manner to the procedure of C. Hansch, B.Schmidhalter, F. Reiter, W. Saltonstall J. Org. Chem., 1956, 21, 265 toafford the intermediate 5-chlorosulfonyl-4-isopropyl-2-methoxybenzoicacid which was converted into the title compound using the method ofProcedure 7.

¹H NMR (DMSO-D₆) δ: 1.30 (6H, d), 3.21 (3H, s), 3.80 (1H, m), 3.94 (3H,s), 7.26 (1H, s), 8.19 (1H, s).

Example 1

N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)benzamideHydrochloride

3-Amino-5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridine (96 mg;0.50 mmol) was dissolved in dry THF (5 ml) and the solution treated withbenzoyl chloride (70.3 mg; 0.50 mmol). The mixture was stirred atambient temperature for 2 h then the precipitate collected byfiltration, washed with THF, diethyl ether and dried in vacuo (132 mg;80%).

¹H NMR (250 MHz (CD₃)₂SO) δ: 1.42 and 1.54 (2×3H, s), 3.02 (3H, brs),3.65 (2H, brm), 4.40-4.70 (2H, brm), 7.60-7.71 (3H, m), 8.00-8.10 (2H,m), 8.18 (1H, brs), 8.91 (1H, brs), 10.60-10.90 (2H, brm, exchangeable);^(m)/_(z) (API⁺); 296.1 (MH+).

Example 2

N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-iso-propylbenzamideHydrochloride

Prepared in a manner similar to that of Example 1, from3-cyano-4-iso-propylbenzoic acid as a white powder (171 mg; 86%).

¹H NMR (250 MHz; (CD₃)₂SO) δ: 1.30 (6H, d, J=7 Hz), 1.33 and 1.46 (2×3H,s), 2.94 (3H, d, J=4 Hz), 3.20-3.70 (3H, brm), 4.30-4.60 (2H, m), 7.73(1H, d, J=8 Hz), 809 (1H, d, J=2 Hz), 8.24 (1H, dd, J=10.2 Hz), 8.40(1H, d, J=2 Hz), 8.83 (1H, d, J=2 Hz); ^(m)/_(z) (API⁺); 363.2 (MH+).

Example 3

N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamideHydrochloride

Prepared in a manner similar to that of Example 1 from4-methoxy-3-trifluoromethyl-benzoic acid. The product was purified bychromatography on SiO₂, eluting with 0.88 aq,ammonia/methanol/dichloromethane (0.5:4.5:95), and converted into thehydrochloride salt by addition of 1M hydrogen chloride in diethyl ether(1 equivalent). The title compound was collected by filtration (98 mg;46%). ¹H NMR (250 MHz, (CD₃)₂SO) δ: 1.36 and 148 (2×3H, s), 2.96 (3H, d,J=3 Hz), 3.40 and 3.70 (2×1H, brm), 3.99 (3H, s), 4.30-4.60(2H, br).7.46 (1H, d, J=9 Hz), 8.10 (1H, d. J=2 Hz), 8.28 (1H, brs), 8.34 (1H, brdd). 8.85 (1H, d, J=2 Hz), 10.60-10.80 (2H, br. exchangeable) ^(m)_(/z)(API⁺); 394.2 (MH+).

Example 4

N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-ethylbenzamideHydrochloride

Prepared in a similar manner to that of Example 3 from3-bromo-4-ethylbenzoic acid and isolated as an off-white powder (104 mg;46%).

¹H NMR (250 MHz; (CD₃)₂SO) δ: 1.25 (31H, t, J=7 Hz), 1.40 and 1.54(2×3H, s), 2.83 (2H, q, J=7 Hz), 3.00 (3H, d, J=4 Hz), 3.30-3.80 (2H,brm), 4.30-4.70 (2H, m), 7.59 (1H, d, J=8 Hz), 8.02 (1H, d, J=8 Hz),8.16 (1H, d, J=2 Hz), 8.26 (1H, d, J=1 Hz), 8.90 (1H, d, J=2 Hz); ^(m/)_(z)(API⁺); 402.1, 404.1 (MH+).

Example 5

N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-ethoxybenzamideHydrochloride

Prepared in a similar manner to that of Example 3 from3-bromo-4-ethoxybenzoic acid and isolated as an off-white powder (100mg; 44%).

¹H NMR (250 MHz: (CD₃)₂SO) δ: 1.42 and 1.55 (2×3H, s), 1.46 (3H, t J=7Hz,), 3/01 (3H, brd). 3.30-3.80 (2H, m), 4.29 (2H, q, J=2 Hz), 4.30-4.70(2H, brm), 7.33 (1H, d, J=9Hz), 8.10(1H. dd, J=9.2Hz), 8.16 (1H, d,J=2Hz), 8.33(1H, d, J=2 Hz), 8.91 (1H, d, J=2 Hz), 10.64 (1H, s.exchangeable). 10.86 (1H, br. exchangeable). ^(m)/_(z)(API⁺); 418.1.420.1 (MH+).

Example 6

N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-chloro-4-iso-propyloxybenzamide Hydrochloride

Prepared in a manner similar to that of Example 3 from3-chloro-4-iso-propyloxybenzoic acid and isolated as an off-white powder(67 mg; 32%).

¹H NMR (250 MHz: (CD₃)₂SO) δ: 1.17 (6H, d, J=6 Hz), 1.22 and 1.50 (2×3H,s), 2.78 (3H, brs), 3.40 (2H, brs), 4.20-4.60 (2H, brm), 4.63-473 (1H,m), 7.18 (1H, d, J=9 Hz), 7.85 (1H, dd, J=9.2 Hz), 7.97 (1H, d, J=2 Hz),8.04 (1H, d, J=2 Hz), 8.75 (1H, d, J=2 Hz); ^(m)/_(z)(API⁺); 388.2.390.2 (MH+).

Example 7

N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthridin-3-yl)-3-bromo-4-iso-propyloxybenzamideHydrochloride

Prepared in a manner similar to that of Example 3 from3-bromo-4-iso-propyloxybenzoic acid and isolated as an off-white powder(224 mg: 82%).

¹H NMR (250 MHz; (CD₃)₂SO) δ: 1.24 (6H, d, J=6 Hz), 1.26 and 1.35 (2×3H,s), 2.89 (3H, brd), 3.30 (2H, brm), 4.20-4.50 (2H, brm), 4.74(1H, m),7.0 (1H, d, J=9 Hz.). 7.90(1H, dd, J=9.2 Hz), 7.92 (1H, d, J=2 Hz), 8.15(1H, d, J=2 Hz), 8.72 (1H, d, J=2 Hz); ^(m)/_(z)(API⁺); 434. 432 (MH+:80%).

Example 8

N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthnridin-3-yl)-3-acetyl-4-iso-propyloxybenzamideHydrochloride

Prepared as described in Example 3 from 3-acetyl-4-iso-propyloxybenzoicacid (222 mg: 1.0 mmol), except that the reaction was performed indicliloromethane and in the presence of triethylamine (101 mg; 1.0 mmol;0. 14 ml). The title compound was isolated as a white powder (247 mg;57%).

¹H NMR [free base] (250 MHz: CD₃OD) δ: 1.22 (6H, s), 1.32 (6H, d J=6Hz), 2.31 (3H, s), 2.44 (2H, s), 2.50 (3H, s), 3.45 (2H, s), 4.77(1H,m), 7.12 (1H, d, J=9 Hz), 7.99 (1H, d, J=2 Hz), 7.95 and 7.99 (1H, dd,J=9.2 Hz), 8.16 (1H, d, J=2Hz), 8.56(1H, d, J=2 Hz); m/z (API)⁺; 396.2(MH+; 80%).

Example 9

N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-ethoxy-3-trifluoromethylbenzamideDihydrochloride

Prepared as described in Example 8 from4-ethoxy-3-trifluoromethylbenzoic acid (237 mg; 1.0 mmol) and isolatedas a white powder (416 mg: 87%).

¹H NMR [free base] (250 MHz: CD₃OD) δ: 1.23 (6H, s), 1.34 (3H, t, J=7Hz), 2.32 (3H, s), 2.45 (2H, s), 3.46 (2H, s), 4.13 (2H, q, J=7 Hz),7.16 (1H, d, J=9 Hz), 7.80 (1H, d, J=2 Hz), 8.09 (2H, m), 8.57 (1H, d,J=2 Hz); m/z (API)⁺; 408.2 (MH+; 80%).

Example 10

N-(8,8-Dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamideHydrochloride

N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamide(172 mg; 0.44 mmol) was suspended in 1,2-dichloromethane (30 ml) and themixture treated with 1-chloroethyl chlioroformate (62.5 mg: 47 ml; 0.44mmol). The mixture was heated at reflux and more chlioroformate addeduntil little or no starting material remained. At this point. thevolatiles were removed under reduced pressure and the residue dissolvedin methanol (30 ml) and heated at reflux for 15 min. The volatiles wereremoved under reduced pressure and the residue treated with a mixture of0.88 aqueous ammonia/methanol/dichloromethane (0.5: 4.5:95) and theresulting, beige solid was collected by filtration. The free base (123mg; 0.32 mmol) was dissolved in methanol (min. vol) and treated with IMhydrogen chloride in diethyl ether (0.32 ml: 0.32 mmol) and the mixturediluted with diethyl ether to turbidity and refrigerated. The titlecompound was obtained as white powder (130 mg: 71%).

¹H NMR [free base] (250 MHz: CD₃OD) δ: 1.37 (6H, s), 3.35 (2H, s), 4.35(2H, s), 7.2 (1H, d, J=9 Hz), 8.07 (1H, d, J=2 Hz), 8.15-8.18 (2H, m.)8.70(1H, d J=2 Hz); m/z (API)⁺; 378.1 (MH+; 100%).

The following examples were prepared using methods decscribed above:

Example 11

N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-methoxybenzamideHydrochloride

¹H NMR [free base] (250 MHz; CD₃OD) δ: 1.04 (6H, s), 2.13 (3H, s), 2.26(2H, s), 3.27 (2H, s), 3.65 (3H, s), 6.84 (1H, d, J=9 Hz), 7.59 (1H, d,J=2 Hz), 7.66 (1H, dd, J=9.2 Hz), 7.88 (1H, d, J=2 Hz), 8.37 (1H, d, J=2Hz); m/z (API)⁺; 425.7. 428 (M+Na+).

Example 12

N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthridin-3-yl)-3-chloro-4-methoxybenzamideHydrochloride

¹H NMR [free base] (250 MHz: CD₃OD) δ: 1.41 (6H, s), 2.50 (3H, s), 2.64(2H, s), 3.56 (2H, s), 4.03 (3H, s), 7.26 (1H, d, J=9 Hz), 7.97-8.09(3H, m), 8.73 (1H, d, J=2 Hz); m/z (API)⁺; 382.1, 84.2 (M+Na)⁺.

Example 13

N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-methoxybenzamideHydrochloride

¹H NMR [free base] (250 MHz; CD₃OD) δ: 1.33 (6H, s), 2.43 (3H, s), 2.56(2H, s), 3.58 (2H, s), 4.03 (3H, s), 7.31 (1H, d, J 9 Hz), 7.90 (1H, d,J=2 Hz), 8.23 (2H, m), 8.66 (1H, d, J=2 Hz); m/z (API)⁺351.1 (MH⁺, 80%),373.2 (M−Na)⁻.

Example 14

N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-ethylbenzamideHydrochloride

¹H NMR [free base] (250 MHz; CD₃OD) δ: 1.10 (9H, m), 2.20 (3H, s), 2.34(2H, s), 2.71 (2H, q, J=8 Hz), 3.36 (2H, s), 7.37 (1H, d, J=8 Hz), 7.70(1H, d, J=2 Hz), 7.93 (1H, dd, J=8.2 Hz), 8.04 (1H, d, J=2 Hz), 8.45(1H, d, J=2 Hz); m/z (API)⁺; 349 (MH⁺).

Example 15

N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-methylbenzamideHydrochloride

¹H NMR [free base] (250 MHz; CD₃OD) δ: 1.23 (6H, s), 2.32, 2.33 (2×3H,s), 2.45 (2H, s), 3.44 (2H, s), 7.30 (1H, d, J=8 Hz), 7.72 (1H, dd,J=8.2 Hz), 7.79 (1H, d, J=2 Hz), 8.02 (1H, d, J=2 Hz), 8.56 (1H, d, J=2Hz); m/z (API⁻); 386.0, 387.9 (M−H)⁻.

Example 16

N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-pivaloylbenzamide

¹H NMR (250 MHz; CDCl₃) δ: 1.36 (6H, s), 1.38 (9H, s), 2.45 (3H, s),2.52 (2H, s), 3.59 (2H, s), 7.55 (1H, t, J=8 Hz), 7.88 (1H, m), 7.97(2H, m), 8.17 (1H, s), 8.44 (1H, d, J=2 Hz); m/z (API⁺); 380.4 (MH⁺;30%).

Example 17

N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-5-chloro-2-methoxy-4-iso-propyloxybenzamideHydrochloride

¹H NMR [free base] (250 MHz; CDCl₃) δ: 1.35 (6H, s), 1.44 (6H, d, J=6Hz), 2.44 (3H, s), 2.51 (2H, s), 3.57 (2H, s), 4.05 (3H, s), 4.66 (1H,m), 6.57 (1H, s), 8.06 (1H, d, J=2 Hz), 8.26 (1H, s), 8.34 (1H, d, J=2Hz); m/z (API⁺); 416.1, 418.2 (M+H])⁺.

Example 18

N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-ethoxybenzamide Hydrochloride

¹ H NMR [free base] (250 MHz; CD₃OD) δ: 1.27 (6H, s), 1.42 (3H, t, J=7Hz), 2.37 (3H, s), 2.50 (2H, s), 3.52 (2H, s), 4.22 (2H, q, J=7 Hz),7.22 (1H, d, J=9 Hz), 7.84 (1H, d, J=2 Hz), 8.16 (2H, m), 8.60 (1H, d,J=2 Hz); m/z (API⁺); 365.1 (M+H)⁺.

Example 19

N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoroacetylbenzamide

¹H NMR (250 MHz; CDCl₃) δ: 1.34 (6H, s), 2.44 (3H, s), 2.51 (2H, s),3.55 (2H, s); 3.99 (3H, s) 7.10 (1H, d, J=8 Hz), 7.93 (1H, d, J=8 Hz),8.23 (2H, brm), 8.44 (1H, brs), 8.51 (1H, d, J=2 Hz) m/z (API⁺); 422.1(MH⁺; 100%).

Example 20

N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)naphthalene-2-carboxamide

¹H NMR (250MHz; CDCl₃) δ: 1.42 (6H, s), 2.61 (3H, s), 2.76 (2H, s), 3.78(2H, s), 3.78 (2H, s), 7.20 (1H, m), 7.50-8.65 (7H, m), 7.95 (1H, d, J=2Hz), 8.46 (1H, s), 8.72 (1H, d, J=2 Hz); m/z (API⁺); 346.1 (MH⁺; 70%).

Example 21

N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-iso-propyloxybenzamideHydrochloride

¹H NMR[free base] (250 MHz;CD₃OD) δ: 1.24 (6H, s), 1.32 (6H, d, J=6 Hz),2.34 (3H, s), 2.48 (2H, s), 3.49 (2H, s), 4.74-4.84 (1H, m), 7.21 (1H,d, J=9 Hz), 7.81 (1H, d, J=2Hz), 8.10 (1H, dd, J=9.2 Hz), 8.14 (1H, d,J=2 Hz), 8.57 (1H, d, J=2 Hz); m/z (API⁺); 379.2 (MH⁺)

Example 22

N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-acetyl-4-ethylbenzamideHydrochloride

¹H NMR [free base] (250MHz; CD₃OD) δ: 0.98 (3H, t, J=7 Hz), 1.11 (6H,s), 2.20 (3H, s), 2.34 (2H, s), 2.41 (3H, s), 2.67 (2H, q, J=7 Hz), 3.34(2H, s), 7.22 (1H, brd, J=8 Hz), 7.70 (1H, brs), 7.78 (1H, brd, J=8 Hz),8.08 (1H, brs), 8.47 (1h, brs); m/z (API⁺); 366.2 (MH⁺)

Example 23

N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-2,3-dihydrobenzofuran-5-carboxamideHydrochloride.

¹H NMR [free base] (250 MHz; CD₃OD) δ: 1.35 (6H, s), 2.44 (3H, s), 2.58(2H, s), 3.26 (2H, t, J=9 Hz), 3.58 (2H, s), 4.64 (2H, t, J=9 Hz), 6.81(1H, d, J=8 Hz), 7.76 (1H, dd, J=8.2 Hz), 7.83 (1H, brs), 7.89 (1H, d,J=2 Hz), 8.67 (1H, d, J=2 Hz); m/z (API⁺); 338.2 (MH⁺)

Example 24

N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-n-butyroyl-4-methoxybenzamideHydrochloride.

¹H NMR [free base] (250 MHz; CD₃OD) δ: 0.71 (3H, t, J=7 Hz), 1.08 (6H,s), 1.42 (2H, m), 2.17 (3H, s), 2.31 (2H, s), 2.72 (2H, t, J=7 Hz), 3.32(2H, s), 3.74 (3H, s), 7.00 (1H, d, J=9 Hz), 7.64 (1H, m), 7.86 (1H, dd,J=9.2 Hz), 7.95 (1H, d, J=2 Hz), 8.41 (1H, d, J=2 Hz); m/z (API⁺); 396.2(MH⁺), 418.2 (M+Na⁻)

Example 25

N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-n-propionylbenzamideHydrochloride.

¹H NMR [free base] (250MHz; CD₃OD) δ: 1.12 (3H, t, J=7 Hz), 1.31 (6H,s), 2.41 (3H, s), 2.54 (2H, ), 3.00 (2H, q, J7 Hz), 3.56 (2H, s), 3.97(3H, s), 7.24 (1H, d, J=9 Hz), 7.88 (1H, d, J=2 Hz), 8.10 (1H, dd, J=9.2Hz), 8.21 (1H, d, J=2 Hz), 8.64 (1H, d, J=2 Hz); m/z (API⁺); 382.2(MH⁺).

Example 26

N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl-iso-butyroyl-4-methoxybenzamideHydrochloride.

1H NMR [free base] (250MHz;CD₃OD) δ: 1.04 (6H, d, 7 Hz), 1.25 (6H, s),2.36 (3H, s) 2.76 (2H, s), 3.40 (1H, m), 3.51 (2H, s), 3.88 (31H, s),7.15 (1H, d, J=8 Hz), 7.82 (1H, d, J=2 Hz), 8.02 (2H, m), 8.58 (1H, d,J=2 Hz); m/z (API⁺); 396.3 (MH⁺).

Example 27

N-(8,8-Dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-ethoxy-3-trifluoromethylbenzamideHydrochloride.

¹H NMR [HCl salt] (250MHz; CD₃OD) δ: 1.53 (3H, t, J=7 Hz), 1.69 (6H, s),3.64 (2H, s), 4.35 (2H, q, J=7 Hz), 4.71 (2H, s), 7.41 (1H, d, J=9 Hz),8.38 (2H, m), 8.70 (1H, d, J=2 Hz), 9.38 (1H, d, J=2 Hz); m/z (API⁻);364.1 [M−Et].

Example 28

N-(8,8-Dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-acetyl-4-iso-propyloxybenzamideHydrochloride.

¹H NMR [free base] (250MHz; CD₃OD) δ: 1.22 (6H, s), 1.34 (6H, d, J=6Hz), 2.53 (3H, s), 2.84 (2H, s), 3.78 (2H. s), 4.76-4.86 (1H, m), 7.15(1H, d, J=9 Hz), 7.99 (1H, d, J=2 Hz), (1H, dd, J=9.2 Hz), 8.18 (1H, d,J=2 Hz), 8.57 (1H, d, J=2 Hz); m/z (API⁺); 382.2 (MH⁺).

Example 29

N-(8,8-Dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-methoxybenzamideHydrochloride.

¹H NMR [HCl salt] (250 MHz; (CD₃)₂SO) δ: 1.27 (6H, s), 3.19 (2H, brs),3.81 (3H, s), 4.22 (2H, brs), 7.14 (1H, d, J=9 Hz), 7.94 (1H, brdd),8.08 (1H, brd), 8.14 (1H, d, J=2 Hz), 8.73 (1H, brd), 9.45-9.70 (2H,brs, exchangeable), 10.53 (1H, brs, exchangeable); m/z (API⁻); 389.8,87.9 (M−H).

Example 30

N-(8,8-Dimethyl-5,6,7,8-tetrahydrof[1,6]naphthyridin-3-yl)-3-chloro-4-methoxybenzamideHydrochloride.

¹H NMR [HCl salt] (250 MHz; (CD₃)₂SO) δ: 1.40 (6H, s), 330 (2H, brs),3.91 (3H, s), 4.33(2H, brs), 7.28 (1H, d, J=8 Hz), 8.02 (1H, dd, J=9.2Hz), 8.11 (1H, d, J=2 Hz), 8.25 (1H, d, J=2 Hz), 8.88 (1H, d, J=2 Hz),9.85 (2H, brs, exchangeable), 10.73 (1H, s, exchangeable); m/z (API⁺);346.1-347.2 (MH⁺; 100%)

Example 31

N-(8,8-Dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-pentafluoroethylbenzamide

¹H NNIR (400 MHz, CDCl₃) δ: 1.32 (6H, s), 2.96 (2H, s), 3.96 (3H, s),4.05 (2H, s), 7.13 (1H, d), 7.93 (1H, s), 8.04 (1H, s) 8.06 (1H, s),8.44 (1H, d); m/z (API−); 430 (M+H)⁻

Example 32

N-(8,8-Dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-iso-propoxy-3-trifluoromethylbenzamide

¹H NMR (400 MHz, CD₃OD) δ: 1.41 (6H, d, J=6 Hz), 1.70 (6H, s), 3.63 (2H,s), 4.71 (2H, s), 4.95 (1H, m—overlapped by solvent), 7.40 (1H, d), 8.32(1H, s), 8.34 (1H, d), 8.73 (1H, s), 9.45 (1H, s); m/z (API+); 408(M+H)⁻

Example 33

N-(8,8-Dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-ethyl-3-trifluoromethylbenzamide

¹H NMR (400 MHz, CD₃OD) δ: 1.35 (3H, t, J=7 Hz), 1.62 (6H, s), 2.96 (2H,q), 3.57 (2H, s), 4.63 (2H, s), 7.68 (1H, d), 8.25 (1H, d), 8.33 (1H,s), 8.57 (1H, s), 9.21 (1H, s); m/z (APT+); 378 (M+H)⁻

Example 34

N-(8,8-Dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-iso-propylbenzamide

¹H NMR (400 MHz, CD₃OD) δ: 1.32 (6H, d, J=6 Hz), 1.65 (6H, s), 3.50 (1H,m), 3.59 (2H, s), 4.67 (2H, s), 7.58 (1H, d), 8.02 (1H, d), 8.26 (1H,s), 8.63 (1H, s), 9.32 (1H, s); m/z (API+); 402, 404 (M+H)⁻

Example 35

N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-chloro-4-ethoxybenzamide

¹H NMR (250 MHz, CDCl₃) δ: 1.36 (6H, s), 1.52 (3H, t, J=7 Hz), 2.45 (3H,s), 2.53 (2H, s), 3.59 (2H, s), 4.19 (2H, q, J=7 Hz), 7.00 (1H, d, J=7Hz), 7.64 (1H, brs), 7.76 (1H, dd, J=7.2 Hz), 7.90 (1H, d, J=2 Hz), 7.98(1H, d, J=2 Hz), 8.42 (1H, d, J=2 Hz); m/z (API⁺); 396.2 (M+Na⁺, 100%),374.2 (MH⁺; 33%).

Example 36

N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-fluoro-4-methoxybenzamide

¹H NMR (400 MHz; CDCl₃) δ: 1.35 (6H, s), 2.44 (3H, s), 2.50 (2H, s),3.56 (2H, s), 3.99 (3H, s), 7.03 (1H, t, J=7 Hz), 7.62 (1H, d), 7.72(1H, s), 7.95 (1H, d, J=2 Hz), 8.40 (1H, d, J=2 Hz); m/z (API⁺); 344.2(MH⁺; 93%).

Example 37

N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-pentafluoroethylbenzamide

¹H NMR (400 MHz; CDCl₃) δ: 1.35 (6H, s), 2.46 (3H, s), 2.51 (2H, s),3.57 (2H, s), 3.96 (3H, s), 7.10 (1H, d, J=7 Hz), 7.71 (1H, s), 7.93(1H, d, J=2 Hz), 8.04 (1H, d), 8.06 (1H, d), 8.44 (1H, d, J 2 Hz); m/z(API⁺); 444 (MH⁺; 90%).

Example 38

N-(8,8-Dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-fluoro-4-methoxybenzamideHydrochloride.

¹H NMR (250 MHz; CDCl₃) [free base] δ: 1.32 (6H, s), 2.20 (2H, s), 3.07(2H, s), 3.96 (3H, s), 4.04 (2H, s), 7.02 (1H, t, J=7 Hz), 7.62 (1H, d),7.64 (1H, d), 7.95 (1H, d, J=2 Hz), 8.44 (1H, d, J=2 Hz); m/z (API⁺);330 (MH⁺; 100%).

Example 39

N-(8,8-Dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-propionylbenzamide.

¹H NMR (250 MHz; CDCl₃) δ: 1.18 (3H, t, J=7 Hz), 1.32 (6H, s), 2.96 (2H,s), 3.05 (2H, q, J=7 Hz), 3.99 (3H, s), 4.05 (2H, s), 7.11 (1H, d, J=7Hz), 7.97 (1H, d, J=2 Hz), 8.11 (2H, d), 8.16 (1H, d), 8.45 (1H, d); m/z(API⁺); 390 (MNa⁺; 93%), 368 (MH⁺80%)

Example 40

N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-indole-2-carboxamide.

¹H NMR (250 MHz; CDCl₃+CD₃OD) δ: 1.34 (6H, s), 2.46 (3H, s), 2.56 (2H,s), 3.60 (2H, s), 7.20-7.90 (6H, m), 8.12 (1H, d, J=2 Hz), 8.40 (1H, d,J=2 Hz), 8.60 (1H, brd, J=8 Hz); m/z (API⁺); 335.2 (MH⁺; 100%)

PHARMACOLOGICAL DATA

1. Binding Assay Method

WO 92/22293 (SmithKline Beecham) discloses compounds havinganti-convulsant activity, including inter alia the compoundtrans-(+)-6-acetyl-4S-(4-fluorobenzoylamino)-3,4-dihydro-2.2-dimethyl-2H-1-benzopyran-3R-ol(hereinafter referred to as Compound A). It has been found that thecompounds of WO 92/22293 bind to a novel receptor obtainable from ratforebrain tissue. as described in WO 96/18650 (SmithKline Beecham). Theaffinity of test compounds to the novel receptor site is assessed asfollows.

Method

Whole forebrain tissue is obtained from rats. The tissue is firsthomogenised in buffer (usually 50 mmM Tris/HCl, pH 7,4). The homogenisedtissue is washed by centrifugation and resuspension in the same buffer,then stored at −70° C. until used.

To carry out the radioligand binding assay, aliquots of tissue preparedas above (usually at a concentration of 1-2 mg protein/ml) are mixedwith aliquots of [3H]-Compound A dissolved in buffer. The finalconcentration of [3H]-Compound A in the mixture is usually 20 nM. Themixture is incubated at room temperature for 1 hour. [3H]-Compound Abound to the tissue is then separated from unbound [3H]-Compound A byfiltration through Whatman GF/B glass fibre filters. The filters arethen washed rapidly with ice-cold buffer. The amount of radioactivitybound to the tissue trapped on the filters is measured by addition ofliquid scintillation cocktail to the filters followed by counting in aliquid scintillation counter.

In order to determine the amount of “specific” binding of [3H]-CompoundA, parallel assays are carried out as above in which [3H]-Compound A andtissue are incubated together in the presence of unlabelled Compound A(usually 3 μM). The amount of binding of [3H]-Compound A remaining inthe presence of this unlabelled compound is defined as “non-specific”binding. This amount is subtracted from the total amount of[3H]-Compound A binding (i.e. that present in the absence of unlabelledcompound) to obtain the amount of “specific” binding of [3H]-Compound Ato the novel site.

The affinity of the binding of test compounds to the novel site can beestimated by incubating together [3H]-Compound A and tissue in thepresence of a range of concentrations of the compound to be tested. Thedecrease in the level of specific [3H-Compound A binding as a result ofcompetition by increasing concentrations of the compound under test isplotted ographically and non-linear regression analysis of the resultantcurve is used to provide an estimate of compound affinity in terms ofpKi value.

Results

Compounds of this invention were active in this test with pKi>6. Forexample, compounds of Examples 2-11 and 25-34 gave pKi values greaterthan 8.

2. MEST Test

The maximal electroshock seizure (MEST) threshold test in rodents isparticularly sensitive for detecting potential anti convulsantproperties ¹. In this model anticonvulsant agents elevate the thresholdto electrically-induced seizures whilst proconvulsants lower the seizurethreshold.

Method for Mouse Model

Mice (naive male, Charles River, U.K. CD-1 strain, 25-30 g) are randomlyassigned to (groups of 10-20 and dosed orally or intraperitoneally at adose volume of 10 ml/kg with various doses of compound (0.3-300 mg/kg)or vehicle. Mice are then subjected at 30 or 60 min post dose to asingle electroshock (0.1 sec. 50 Hz sine wave form) administered viacorneal electrodes. The mean current and standard error required toinduce a tonic seizure in 50% (CC₅₀) of the mice in a particulartreatment group is determined by the ‘up and down’ method of Dixon andMood (1948)². Statistical comparisons between vehicle- and drugy-treatedgroups are made using the method of Litchfield and Wilcoxon (1949)³.

In control animals the CC₅₀ is usually 14-18 mA. Hence the first animalin the control group is subjected to a current of 16 mA. If a tonicseizure does not ensue, the current is increased for a subsequent mouse.If a tonic convulsion does occur, then the current is decreased, and soon until all the animals in the group have been tested.

Studies are carried out using a Hugo Sachs Electronik Constant CurrentShock Generator with totally variable control of shock level from 0 to300 mA and steps of 2 mA are usually used.

Method for Rat Model

The threshold for maximal (tonic hindlimb extension) electroshockseizures in male rats (Sprague Dawley, 80-150 g 6 weeks old) wasdetermined by a Hugo Sachs Electronik stimulator which delivered aconstant current (0.3 sec duration; from 1-30 mA in steps of 5-20 mA).The procedure is similar to that outlined above for mouse and fulldetails are as published by Upton et al,.⁴

The percentage increase or decrease in CC₅₀ for each group compared tothe control is calculated. Drugs are suspended in 1% methyl cellulose.

Results

At a dosage of 2 mg/kg p.o. at 2 h, the compounds of Examples 3 and 5showed increases in the rat model of 314% and 350% respectively.

References

1. Loscher, W. and Schmidt, D. (1988), Epiiepsy Res., 2A 145-181

2. Dixon, W. J. and Mood, A. M. (1948), J. Amer. Stat. Assn., 43,109-126

3. Litchfield, J. T. and Wilcoxon, F. (1949), J. Pharmacol. exp. Ther.,96. 99-113

4. N. Upton. T. P. Blackburn, C. A. Campbell, D.Cooper, M. L. Evans, H.J. Herdon, P. D. King, A. M. Ray, T. O. Stean, W. N. Chan. J. M. Evansand M. Thompson. (1997), B. J. Pharmacol., 121. 1679-1686

What is claimed is:
 1. A compound selected from the group consisting of:N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)benzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-iso-propylbenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-ethylbenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-ethoxybenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-chloro-4-iso-propyloxybenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-iso-propyloxybenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-acetyl-4-iso-propyloxybenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-ethoxy-3-trifluoromethylbenzamide;N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-methoxybenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-chloro-4-methoxybenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-methoxybenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-ethylbenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-methylbenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-pivaloylbenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-5-chloro-2-methoxy-4-iso-propyloxybenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-ethoxybenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoroacetylbenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)naphthalene-2-carboxamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-iso-propyloxybenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-acetyl-4-ethylbenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-2,3-dihydrobenzofuran-5-carboxamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-n-butyroyl-4-methoxybenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-n-propionylbenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl-iso-butyroyl-4-methoxybenzamide;N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-ethoxy-3-trifluoromethylbenzamide;N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-acetyl-4-iso-propyloxybenzamide;N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-methoxybenzamide;N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-chloro-4-methoxybenzamide;N-(8,8-dimethyl-5,6,7,8-tetrahydro1,6]naphthyridin-3-yl)-4-methoxy-3-pentafluoroethylbenzamide;N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-iso-propoxy-3-trifluoromethylbenzamide;N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-ethyl-3-trifluoromethylbenzamide;N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-iso-propylbenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-chloro-4-ethoxybenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-fluoro-4-methoxybenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-pentafluoroethylbenzamide;N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-fluoro-4-methoxybenzamide;N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-propionylbenzamide,and;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-indole-2-carboxamide.2. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 3. A method of treatment and/orprophylaxis of anxiety, mania, depression, panic disorders and/oraggression, disorders associated with a subarachnoid hemorrhage orneural shock, the effects associated with withdrawal from substances ofabuse such as cocaine, nicotine, alcohol and benzodiazepines, disorderstreatable and/or preventable with anti-convulsive agents, epilepsy,post-traumatic epilepsy, Parkinson's disease, psychosis, migraine,cerebral ischaemia, Alzheimer's disease and other degenerative diseasessuch as Huntingdon's chorea, schizophrenia, obsessive compulsivedisorders, neurological deficits associated with AIDS, sleep disorders,circadian rhythm disorders, insomnia, narcolepsy, tics, Giles de laTourette's syndrome, traumatic brain injury, tinnitus, neuralgia,especially trigeminal neuralgia, neuropathic pain, dental pain, cancerpain, diabetes, multiple sclerosis, motor neuron disease, ataxias,muscular rigidity, temporomandibular joint dysfunction, and amyotrophiclateral sclerosis comprising administering to the sufferer in needthereof an effective or prophylactic amount of a compound according toclaim
 1. 4. A process for the preparation of compounds according toclaim 1 which comprises reacting a compound of formula (II)

where R^(1A), R^(3A), R^(4A), X are R¹, R³, R⁴, X as defined for formula(I) or a group or groups convertible to R¹, R³, R⁴, X with a compound offormula (III)

where is a leaving group, and R^(2A) groups are independently R² asdefined for formula (I) or a group or groups convertible to R², andwhere required converting an R^(1A), R^(2A), R^(3A), R^(4A), X group toa R¹, R², R³, R⁴, X group, converting one R¹, R², R³, R⁴, X group toanother R¹, R², R³, R⁴, X group, or converting a salt product to thefree base or another pharmaceutically acceptable salt, or separating anyenantiomers, or converting a free base product to a pharmaceuticallyacceptable salt.